Development and Evaluation of a polymer coated proprietary cream formulation of resiniferatoxin nanoparticles for the Treatment of Pain Associated with Diabetic Peripheral Neuropathy Diabetes is a major problem in developed and developing countries. It is estimated that 450 million adults will have diabetes globally by year 2030. One of the major complications of diabetes is diabetic peripheral neuropathy (DPN) resulting in pain from the extremities referred to as painful DPN (PDPN). Treatment options include centrally acting drugs such as antidepressants, anticonvulsants and opioids and topical agents. Addiction and over-dose have become serious problems while treating painful conditions with opioids. For the past 20 years, we have been working on Transient Receptor Potential Vanilloid 1 (TRPV1) receptor, an ion channel expressed in the peripheral terminals of sensory neurons that is activated by capsaicin, an ingredient in hot chili pepper. TRPV1 is considered as a target for next generation analgesics. Potent antagonists have been synthesized and shown to be effective in clinical trials. Unfortunately, TRPV1 antagonists induced hyperthermia in clinical trials leading to their abandonment as a therapeutic armamentarium. However, TRPV1 agonists have been useful to treat painful conditions by virtue of their ability to cause calcium influx leading to nerve terminal desensitization/depletion. Recently, an eight percent capsaicin containing patch (Qutenza) has been approved for the treatment of PDPN in Europe. Since activation of TRPV1 depolarizes the nerve terminal and generates action potentials leading to pain, lidocaine, a local anesthetic is applied to numb the area prior to application of capsaicin patch. We have been working on an ultrapotent TRPV1 agonist, resiniferatoxin (RTX), obtained from the spurge Euphorbia resinifera, which has a high affinity for the receptor and able to fully activate the receptor in femtomolar concentration ranges. Therefore, lower concentrations can activate the channel slowly in a ramp-like fashion avoiding rapid depolarization and preventing generation of action potentials, as a result RTX cream does not induce pain during application. In Aim 1, we will prepare a polymer coated proprietary cream formulation of RTX nanoparticles, for which we have intellectual property rights and trade marked as (NanoResinizinTM). In Aim 2, we will determine the lowest effective concentration range of RTX in the cream formulation by topical application in animal models (rats and pigs) of diabetes that alleviates pain associated with DPN. We will use radiant heat and a state of the art Diode laser fiber type selective stimulation (DLss) approach for A? or C fibers. This method can be applied effectively in humans during the phase II of the translational phase. We propose that NanoResinizinTM cream will be cost effective and can replace the use of capsaicin (8%) plus lidocaine to treat painful conditions, use of which is both cumbersome and associated with significant side effects. Since the last submission, we have prepared the RTX cream formulation and provide evidence using in-vitro skin membrane preparations that RTX diffuses well across the skin (Fig.3).